It is generally believed that cardiogenic pulmonary edema results solely from pulmonary microvascular hypertension. Several recent studies, however, indicate that after coronary ligation, other mechanisms are operative. The purpose of the proposed research is to test the hypothesis that increased microvascular permeability is in part responsible for pulmonary edema after coronary ligation. Chronically-instrumented sheep with lung lymph fistulae will be studied before and after coronary ligation. The response to coronary ligation of protein clearance and extravascular lung water volume will be compared to their response to microvascular pressure manipulation. If increased permeability is not thereby confirmed, the role of primary changes in interstitial compliance and lymphatic propulsion will be investigated in anesthetized sheep, by measuring lymph flow and composition and by determining interstitial volume and the albumin-excluded fraction of the interstitial space in serial lung biopsies before and after coronary ligation. If increased permeability is confirmed, we will begin preliminary studies investigating the possible mediation of increased sympathetic tone, proteases, bradykinin, and prostaglandins, by blocking their activities and separate groups of sheep undergoing coronary ligation.